title: Human glutathione S-transferase deficiency as a marker of susceptibility to epoxide-induced cytogenetic damage.
abstract: The identification of genetic traits that predispose individuals to environmentally induced cancers is one of the most important problems in cancer risk assessment. Genetic deficiency in the mu-isozyme of the glutathione (GSH) S-transferases (EC 2.5.1.18) has recently been associated with increased lung cancer risk. To test whether this association could arise from a metabolically mediated sensitivity to mutagenic substrates, cytogenetic damage in lymphocytes from 21 isozyme-deficient and 24 nondeficient individuals was induced. Cells were treated with trans-stilbene oxide, an excellent substrate for GSH S-transferase mu, or cis-stilbene oxide, a poor substrate for the isozyme. Sister chromatid exchange induction was measured as an indicator of cytogenetic damage. A trimodal distribution of trans-stilbene oxide-induced sister chromatid exchanges was observed in the population, including resistant, moderate, and highly sensitive groups. Glutathione S-transferase mu deficiency was associated with both moderate and high sensitivity to trans-stilbene oxide-induced damage but had no effect on cis-stilbene oxide-induced sister chromatid exchange. The results indicate that GSH S-transferase mu, a proposed marker of cancer susceptibility, is also a marker of susceptibility to the induction of cytogenetic damage by a certain class of mutagens. The differential effects of the cis- and trans-isomers of stilbene oxide illustrate that the stereoselectivity of GSH S-transferase mu toward various alkene epoxide substrates can be an important factor affecting individual sensitivity to DNA-damaging epoxides.
authors.affiliation: Department of Epidemiology and Biostatistics, School of Medicine, University of California, San Francisco 94143.
authors.forename: J K
authors.initials: JK
authors.lastname: Wiencke
authors.forename: K T
authors.initials: KT
authors.lastname: Kelsey
authors.forename: R A
authors.initials: RA
authors.lastname: Lamela
authors.forename: W A
authors.initials: WA
authors.lastname: Toscano
mesh_terms: D000328:Adult; D000368:Aged; D055598:Chemical Phenomena; D002621:Chemistry; D004305:Dose-Response Relationship, Drug; D005260:Female; D005982:Glutathione Transferase / Q000172:deficiency*; D006801:Humans; D007527:Isoenzymes / Q000172:deficiency*; D008214:Lymphocytes / Q000166:cytology / Q000201:enzymology*; D008297:Male; D012854:Sister Chromatid Exchange / Q000187:drug effects*; D013267:Stilbenes / Q000009:adverse effects*
chemical_list: D007527:Isoenzymes; D013267:Stilbenes; D005982:Glutathione Transferase; C025906:stilbene oxide